Posttraumatic stress disorder (PTSD) is a complex anxiety disorder that develops following exposure to either military or civilian traumatic stress. PTSD affects approximately 10% of women and 5% of men in the US, and affected individuals are at increased risk for unemployment, depression, substance abuse, and impaired physical health. PTSD is overrepresented in Veterans. Family and twin studies have implicated both genetic and environmental factors in PTSD risk. Case/control studies have identified associations between PTSD risk and variants in a number of candidate genes; however, such associations have not been consistently replicated in multiple independent datasets. We hypothesize that this difficulty in replication is the result of the failure of previous studies to include epigenetic variation, an to fully account for gene/environment interactions. The present application will address this gap in our knowledge of the factors that increase risk of PTSD. We have an existing genome-wide association dataset of more than 2500 PTSD cases and controls (including 1470 African Americans), genotyped at more than 2.5 million genetic variants. We will conduct association studies in this dataset, and incorporate environmental influences in our genetic models. We will measure epigenetic variation in 1470 African American PTSD patients and controls, using the Illumina methylation arrays that measure DNA methylation levels at more than 480,000 sites across the genome. This methylation data will be analyzed independently, as well as in conjunction with genetic data, to determine its role in PTSD risk. Finally, we will conduct an exploratory gene*environment and epigenome*environment interaction analysis. By including environmental and epigenetic factors in our analysis of genetic variants, we stand to gain a much clearer understanding of the multiple factors that increase both the risk and severity of PTSD.